Process for the isolation of crystalline imipenem

ABSTRACT

The present invention relates to a cost effective and industrially advantageous process for the preparation of imipenem of high purity comprising the steps of treating an aqueous solution containing imipenem with an organic solvent, wherein the imipenem is not lyophilized; and isolating the pure crystalline imipenem monohydrate from the reaction mixture thereof.

FIELD OF THE INVENTION

The present invention relates to a cost effective and industriallyadvantageous process for the preparation of imipenem of high purity.

BACKGROUND OF THE INVENTION

Imipenem monohydrate is the N-formimidoyl derivative of thienamycin, andhas the structural Formula I.

It is the first clinically available member of a new class of β-lactamantibiotics that possess the carbapenem ring system. Imipenem exhibitsan extremely broad spectrum of activity against gram-positive andgram-negative aerobic and anaerobic species, which is partly due to itshigh stability in the presence of β-lactamases.

Imipenem was first disclosed in U.S. Pat. No. 4,194,047 and was obtainedby lyophilization technique. The product obtained by lyophilization isfound to be largely amorphous and stated to be thermodynamicallyunstable. The process also involves an initial purification throughcolumn chromatography using hydrophobic resins.

A thermodynamically stable crystalline monohydrate form of imipenem isdisclosed in U.S. Pat. No. 4,260,543 which is obtained bycrystallization of a lyophilized sample of imipenem. However, thisprocess is not satisfactory on a commercial scale as it requiresisolation of the product by column chromatography, lyophilization,followed by crystallization. Moreover, the prolonged process forisolation of the final product leads to degradation of imipenem, thusaffecting the purity of the product.

U.S. Pat. No. 4,292,436 discloses crystalline imipenem by purifying thecrude product by column chromatography. Further, Crocker et al. havereported in J. Pharm. Sci. 84, 226 (1995) that changes in lyophilizationparameters result in varying degrees of crystallinity in the isolatedimipenem samples. A variant method for preparing imipenem having a highdegree of crystallinity by freeze crystallization process has beenreported by Connolly et. al. in J. Pharm. Sci, 85, 174(1996). However,these processes are tedious, cumbersome and unsuitable for industrialuse.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a simple, practicaland efficient method for the preparation of crystalline imipenemmonohydrate which is thermally stable, has a uniform degree ofcrystallinity and high purity.

The present invention relates to a process for the isolation of purecrystalline imipenem monohydrate from a solution containing imipenem.The process does not use capital intensive techniques of lyophilizationor freeze crystallization as well as the time consuming purificationprocess of column chromatography using expensive hydrophobic resins. Thepresent invention thus fulfills the need for a process which isconvenient to operate on a commercial scale.

Accordingly, the present invention provides a process for the isolationof pure crystalline imipenem monohydrate of Formula I,

which comprises crystallizing imipenem monohydrate from a solutionthereof which contains an organic, aqueous solvent or a mixture thereof,without using lyophilization, freeze drying or chromatographictechniques.

The solvent system from which the product may be crystallized willdesirably be selected from organic solvents which are water-miscibleorganic solvents, either alone or in admixture with water.

Examples of such water-miscible organic solvents include lower alcoholssuch as methanol, ethanol, propanol and isopropanol; ketones such asacetone; glycol ethers such as monoethylene glycol; amides such asN,N-dimethylformamide, N,N-dimethylacetamide; lactams such asN-methylpyrrolidone and cyclic ethers such as tetrahydrofuran, dioxane,or mixture(s) thereof.

The crystallization step will desirably be carried out at lowtemperatures, for example at about 0° C. to about 15° C., and theconcentration of imipenem in the solution from which crystallizationwill occur will generally be adjusted e.g. by evaporation of the solventor by dilution so as to be neither too dilute nor too concentrated.

The crystallization may comprise the last stage or stages of a reactionin which the imipenem is formed. The reaction in which the imipenem isformed may be carried out by following any of the synthetic routesdescribed in the prior art viz. U.S. Pat. Nos. 4,194,047; 4,292,436;4,374,772; or 4,894,450 and are incorporated herein by reference, butwill preferably be carried out in the manner described in the patentapplication filed concurrently herewith and exemplified as example 1 inthis patent application.

Before carrying out the process of crystallization, the solutioncontaining imipenem may be washed with an organic solvent having limitedmiscibility in water to remove organic impurities.

Also, pH of the solution of imipenem is adjusted, if required, to about7 to 8 before washings to facilitate removal of impurities.

In the meaning of the present invention, the term “limited miscibility”shall also include water-immiscible solvents. Examples of such organicsolvents include carboxylic acid esters such as ethyl acetate, higheralkyl ketones such as methylisobutyl ketone, chlorinated hydrocarbonssuch as dichloromethane, ethers such as diethyl ether, aromatichydrocarbons such as toluene, and mixture(s) thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the following section preferred embodiments are described by way ofexamples to illustrate the process of the invention. However, these arenot intended in any way to limit the scope of the present invention.

PREPARATION OF IMIPENEM Example 1

Step (a)—Preparation of enol phosphate intermediate

p-Nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(1 R)-1 -hydroxyethyl)]carbapenem-3-carboxylate (30 g) was dissolved in a mixture ofN,N-dimethylacetamide (300 ml) and dichloromethane (150 ml). Thesolution was cooled to −55° C. and dimethylaminopyridine (0.17 g) wasadded followed by diisopropylethylamine (26.7 g). The mixture wasstirred for 5 minutes at about −55° C. and then a solution ofdiphenylchlorophosphate (25.4 g) in dichloromethane (30 ml) was addeddropwise at −55 to −45° C. The reaction was stirred further for 30minutes to obtain the enol phosphate ester.

Step (b)—Preparation of thienamycin ester

The reaction mixture from step (a) was further cooled to −70 to −75° C.and a solution of 2-aminoethanethiol hydrochloride (12 g) inN,N-dimethylacetamide (60 ml) was added in 10 minutes at −75 to −60° C.The reaction mixture was stirred for another 60 minutes to producep-nitrobenzyl ester of thienamycin.

Step (c)—Preparation of p-nitrobenzyl ester of imipenem

To the above reaction mixture from step (b), was addeddiisopropylethylamine (16.0 g) and benzyl formimidate hydrochloride(20.0 g) at −50 to −55° C. The reaction was allowed to continue forabout one and a half hour at the same temperature. The temperature wasthen raised to −20° C. and the reaction mixture was stirred for 20-30minutes at this temperature to obtain a clear solution of imipenemester.

Step (d)—Preparation of imipenem

The above clear solution obtained from step (c) was poured into amixture of water (300 ml), isopropanol (150 ml) and N-methylmorpholine(26 g) maintained at 5-10° C. and the pH of the solution adjusted to 7.0to 7.5. The solution was hydrogenated at 3-4 kg pressure for 2.5 hoursat 10-25° C. over palladium-charcoal. The mixture was filtered andassayed for imipenem (80%, as determined by HPLC).

ISOLATION OF CRYSTALLINE IMIPENEM MONOHYDRATE Example 2

The reaction mixture containing imipenem obtained at step (d) Example 1was stirred with dichloromethane (900 ml) maintaining pH between 7.0 to8.0 and the aqueous layer separated. The aqueous portion was degassed toremove dichloromethane and given activated carbon treatment. Thefiltered aqueous solution was mixed with isopropanol (400 ml) andstirred at 5-10° C. for 3 hours. The crystalline product so obtained wasfiltered, washed with isopropropanol followed by acetone and dried at35-40° C. for 1 hour to obtain crystalline imipenem monohydrate (9.0 g,purity 99% by HPLC).

Example 3

The process of Example 2 was repeated using acetone (400 ml) instead ofisopropanol during crystallization. Crystalline imipenem monohydrate(8.0 g) was obtained in 99% purity (by HPLC).

Example 4

The aqueous portion obtained as in Example 2 was concentrated to 200 ml.The aqueous solution so obtained was given carbon treatment at 5-10° C.and the filtered solution was stirred with acetone (400 ml) at 5-10° C.for 3 hours to obtain crystalline imipenem monohydrate after filtrationand drying (12.0 g, purity 98-99% by HPLC).

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A process for the preparation and isolation of pure crystallineimipenem monohydrate of Formula I, having a purity of 98% or more byHPLC, the process comprising:

(a) treating an aqueous solution containing imipenem with an organicsolvent to get a mixture, wherein the imipenem is not lyophilized; (b)stirring the mixture; and (c) isolating the pure crystalline imipenemmonohydrate from the mixture.
 2. The process of claim 1 wherein theorganic solvent comprises a water-miscible organic solvent.
 3. Theprocess of claim 2 wherein the water-miscible organic solvent isselected from the group consisting of methanol, ethanol, propanol,isopropanol, acetone, monoethylene glycol, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, dioxane andmixture(s) thereof.
 4. The process of claim 1 wherein the stirring iscarried out at a temperature from about 0° C. to about 15° C.
 5. Theprocess of claim 1 wherein the solution containing imipenem is obtaineddirectly from a reaction mixture.
 6. The process of claim 1 wherein thesolution containing imipenem is washed with a solvent comprising one ormore of a carboxylic acid ester an alkyl ketone having six or morecarbons, chlorinated hydrocarbon, ether, aromatic hydrocarbon, or amixture thereof prior to treating with an organic solvent.
 7. Theprocess of claim 6 wherein the solvent is selected from the groupconsisting of ethyl acetate, methylisobutyl ketone, dichloromethane,diethyl ether, toluene and in mixture(s) thereof.
 8. The process ofclaim 6 wherein the pH of the solution is adjusted to about 7 to 8before carrying out the washing.